This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-HL-104: Characterize the role and effects of the respiratory and/or intestinal microbiota on the presence and clinical phenotype of lung disease. The progressive lung disease that is the primary cause of illness and death in persons with cystic fibrosis (CF) is strongly influenced by immunological defense mechanisms in the airways, and a major contributor to an individual's immune response is the microorganisms that have established themselves in the airways. Currently, very little is known about the microbiota of the respiratory tract in persons with CF or the relationship of lung disease to changes in the microbial community of the airways. A mission of the National Heart, Lung and Blood Institute is to better understand the relationships between individual microbiomes and lung disease. This understanding will not only provide important insights into the causes and mechanisms of lung disease, but also offer great potential for rapid translation of research results into improved approaches for prevention and treatment of CF lung disease. The long-term objective of this project is to understand the relationship between the lung microbiota and the progression of lung disease in persons with cystic fibrosis (CF). We will analyze a large existing repository of sputum samples obtained from several hundred CF patients during the past decade. We will utilize culture-independent analysis of the microbial community in the CF lung analyses to characterize the lung microbiota of these individuals and correlate changes in airway microbial community to changes in patient clinical status. Comparison of microbial community structure within individual patients during periods of relative health and illness, and between patients with similar or different clinical status will be done to associate specific ecologic and functional characteristics of the lung microbiota with the progression of CF lung disease. PUBLIC HEALTH RELEVANCE: Progressive lung disease, resulting from chronic infection of the airways, is the primary cause of illness and death in persons with cystic fibrosis (CF). Recent studies indicate that the number of microbial species involved in lung infection in CF (the CF lung microbiota) is much larger and more complex than previously believed. Nevertheless, currently little is known about how the structure of the lung microbiota (i.e., the precise types of species present and the relative abundance of each) or changes in this structure influence the progression of lung disease in CF. The long-term objective of this project is to understand the relationship between the lung microbiota and the progression of lung disease in persons with CF.